PB1800: CLINICAL CHARACTERISTICS AND MUTATION LANDSCAPE OF TRISOMY AML
Authors: Stephen S Y Lam, Christy Sp Tsui, Cy Fung, Nicole Y Saw, Asif Javed, Anskar Yh Leung
Journal: HemaSphere (2023)

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Acute myeloid leukaemia (AML) is a group of heterogeneous diseases. Disease prognostication is largely dictated by cytogenetic subgroups and recurrent mutations based on next generation sequencing. AML with trisomy as the sole chromosomal abnormalities constitutes around 6-8% of all cases. While the mutation landscape of cytogenetically normal (CN) AML has been characterised, information pertaining to trisomy AML is relatively scarce. Aims: We aim to delineate the clinical characteristics and genomic landscape of young patients with AML carrying one or more trisomy as the sole cytogenetic abnormalities and performed a comparative study with those of CN-AML. Methods: We examined the clinical outcome of adult AML patients treated in Queen Mary Hospital, Hong Kong from 1999 to 2022 and focused on those with one or multiple trisomies at diagnosis. Targeted sequencing of 544 genes (Pan Cancer Panel) were performed in patient samples from whom diagnostic samples were available. Results: Clinicopathologic characteristics of 2324 patients were reviewed, of whom 130 (5.6%) of them carried one or more multiple trisomies as the sole karyotype abnormalities. Chromosomes 8, 11 and 21 were most frequently involved (Fig. A). Double trisomies were observed in 16 patients, of whom chromosomes 8, 11 and 19 were most frequently involved. Ninety-four patients received induction anthracycline-based chemotherapy with “7 + 3” regimen. Complete remission (CR) was achieved in 60 (63.8%) patients, with no significant difference among different trisomy subgroups (Fig. B). Thirty-three patients received allogeneic haematopoietic stem cell transplantation (HSCT). Progression-free survival (PFS, censored at HSCT) was 1.4 years (median, 39% at 5 years, and 39% at 10 years) (Fig. C). Overall survival (OS) was 2.0 years (median, 33% at 5 years, 29% at 10 years) (Fig. D). There was no significant difference in CR rate, PFS and OS between CN and trisomy AML. Targeted sequencing was performed in 112 trisomy AML patients. Recurrent mutations were identified in genes involved in chromatin remodelling (ASXL1), epigenetics (DNMT3A, IDH1/2, TET2), signalling (NRAS, FLT3-ITD, KRAS), transcription factor (ZNF469, RUNX1), cytoskeleton (OBSCN, SYNE1, UBR4) and spliceosome (SRSF2) (Fig. E). Compared with CN-AML, mutations of NRAS (25.9% vs 9.5%, p<0.0001), KRAS (15.2% vs 3.3%, p<0.0001), RUNX1 (19.6% vs 9.3%, p<0.005), SRSF2 (17.9% vs 4.3%, p<0.0001), ASXL1 (17.0% vs 6.3%, p<0.001), STAG2 (15.2% vs 4.0%, p=0.0001), BCOR (14.3% vs 3.8%, p=0.0002) and BCORL1 (11.6% vs 1.8%, p=0.0000) occurred more frequently in trisomy AML, whereas those in NPM1 (14.3% vs 42.6%, p<0.0001) and CEBPa (2% vs 12%, p<0.0001) occurred less frequently.Summary/Conclusion: AML with trisomy karyotype embraces a heterogeneous group of AML with diverse cytogenetic and mutation profile distinct from CN-AML. The mechanistic link between specific mutations, chromosomal aberrations and therapeutic responses would have to be further examined. Keywords: Genetic, Prognosis, AML, Cytogenetic abnormalities